Abstract
The pig is commonly used as an experimental model of human heart disease, including for the study of mechanisms of arrhythmia. However, there exist differences between human and porcine cellular electrophysiology: The pig action potential (AP) has a deeper phase-1 notch, a longer duration at 50% repolarization, and higher plateau potentials than human. Ionic differences underlying the AP include larger rapid delayed-rectifier and smaller inward-rectifier K+-currents (IKr and IK1 respectively) in humans. AP steady-state rate-dependence and restitution is steeper in pigs. Porcine Ca2+ transients can have two components, unlike human. Although a reliable computational model for human ventricular myocytes exists, one for pigs is lacking. This hampers translation from results obtained in pigs to human myocardium. Here, we developed a computational model of the pig ventricular cardiomyocyte AP using experimental datasets of the relevant ionic currents, Ca2+-handling, AP shape, AP duration restitution, and inducibility of triggered activity and alternans. To properly capture porcine Ca2+ transients, we introduced a two-step process with a faster release in the t-tubular region, followed by a slower diffusion-induced release from a non t-tubular subcellular region. The pig model behavior was compared with that of a human ventricular cardiomyocyte (O'Hara-Rudy) model. The pig, but not the human model, developed early afterdepolarizations (EADs) under block of IK1, while IKr block led to EADs in the human but not in the pig model. At fast rates (pacing cycle length = 400 ms), the human cell model was more susceptible to spontaneous Ca2+ release-mediated delayed afterdepolarizations (DADs) and triggered activity than pig. Fast pacing led to alternans in human but not pig. Developing species-specific models incorporating electrophysiology and Ca2+-handling provides a tool to aid translating antiarrhythmic and arrhythmogenic assessment from the bench to the clinic.
Highlights
The pig is commonly used in experimental models to study mechanisms of life-threatening arrhythmias that lead to sudden cardiac death (SCD) in humans [1,2,3,4], and to analyze the role of modulating factors, because its cardiac action potential (AP) duration (APD) and heart size are similar to those of humans
We developed a computational model of pig ventricular cardiomyocyte AP based on available and new experimental characterizations of cellular electrophysiology and Ca2+ handling
Extensive cardiac electrophysiological data exist at the tissue/whole-heart scale for experimental pig models used to study arrhythmogenesis, limited data exist at the cell-scale
Summary
Computational models of ventricular cardiomyocyte APs have been very successful in explaining arrhythmia mechanisms, altered function and drug therapy mechanisms during cardiac pathologies such as myocardial infarction (MI) [11], heart failure [12], gene mutations affecting ion channel subunits [13], drug therapy [14] and ischemia/hypoxia [15]. These models integrate multiple experimental data-sets of ion channel, ion pump and exchanger function, as well as intracellular ionic sub-compartment handling in ventricular myocytes. Without computational models to understand the underlying differences between the cardiomyocytes of these two species translating results is very difficult
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